Among the numerous steps required for an immunological response to occur is the presentation of the antigen by macrophages to the B-cell or T-cell. This presentation is mediated by the Class I and Class II major histocompatibility complex (MHC) molecules on the surface of the cell. The MHC molecules hold antigens in the form of the peptide fragments and together with the receptor molecule on the T-cells, form a macromolecular complex that induces a response in the T-cell. Therefore, a necessary step in an immune response is the binding of the antigen to the MHC.
Recent single crystal X-ray structures of human and murine Class I MHC's have been reported. Analysis of these crystal structures have shown that antigenic peptides lie in the so-called binding cleft for presentation to the T-cell. This cleft is formed by α1 and α2 domains and by β-strands from each domain forming the floor. Furthermore, the sequence polymorphism among Class I molecules can result in alterations of the surface of the cleft forming different pockets. Peptide side chains may insert into these pockets. Thus, different pockets may interact with different side chains. This implies the mechanism for the peptide specificity of class I MHC's. Peptides bound to the Class I MHC's in the crystal structures were found to have both the amino and carboxy termini tightly held by the MHC. There were few interactions near the middle of the cleft. Hence the bound peptide is allowed to bend slightly in the center. The observed binding mode helped to explain the apparent partial specificity of peptide sequence and the allowed variation in peptide length found among peptides isolated from Class I MHC's.
The precise mode of binding of peptides to Class II MHC molecules is less clear. While a single crystal X-ray diffraction structure for the HLA-DR1 MHC has been shown, the coordinates have remained unavailable. However, currently available theoretical and experimental results help form a hypothesis that the binding of a peptide to Class II MHC is similar to that observed with Class I. First, it is noted that the Class II binding cleft is structurally similar to that of Class I. This was concluded based upon a sequence analysis of 26 Class I and 54 Class II amino acid sequences.
Unlike with Class I molecules, self-peptides isolated from murine I-Ab and I-Eb, from murine I-Ad and from human HLA-DR1 molecules were found to be varied in size (13 to 25 residues long). The peptides isolated from the murine I-Ab and I-Eb molecules had heterogenous carboxy termini while those from I-Ad and HLA-DR1 had ragged termini at both ends. The varying lengths indicate that the amino and carboxy termini of the peptides were not critical for the binding. One or both termini may protrude from the binding site and be available for further processing. The residues critical for binding were proposed to be at the ends of the peptide as opposed to the center.